Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets

Abstract

In Diabetes, the chronic hyperglycemia and associated complications affecting peripheral nerves are one of the most commonly occurring microvascular complications with an overall prevalence of 50-60%. Among the vascular complications of diabetes, diabetic neuropathy is the most painful and disabling, fatal complication affecting the quality of life in patients. Several theories of etiologies surfaced down the lane, amongst which the oxidative stress mediated damage in neurons and surrounding glial cell has gained attention as one of the vital mechanisms in the pathogenesis of neuropathy. Mitochondria induced ROS and other oxidants are responsible for altering the balance between oxidants and innate antioxidant defence of the body. Oxidative-nitrosative stress not only activates the major pathways namely, polyol pathway flux, advanced glycation end products formation, activation of protein kinase C, and overactivity of the hexosamine pathway, but also initiates and amplifies neuroinflammation. The cross talk between oxidative stress and inflammation is due to the activation of NF- κ B and AP-1 and inhibition of Nrf2, peroxynitrite mediate endothelial dysfunction, altered NO levels, and macrophage migration. These all culminate in the production of proinflammatory cytokines which are responsible for nerve tissue damage and debilitating neuropathies. This review focuses on the relationship between oxidative stress and neuroinflammation in the development and progression of diabetic neuropathy.

Figure 1

Pathophysiology of diabetic neuropathy. Hyperglycemia activates numerous metabolic pathways like polyol pathway, protein kinase c (PKC) pathway, advanced glycation end products (AGE) pathway, and hexosamine pathway. All these pathways are known to integrate through hyperglycemia mediated mitochondrial ROS production. Oxidative stress and these classical pathways in combination activate transcription factors such as nuclear factor kappa enhancer of B cells (NF-κB) and speciality protein-1 (SP-1), resulting in neuroinflammation and vascular impairment. Further, these pathways combined with dysfunctional mitochondria mediated apoptosis or bioenergetic depletion can lead to neuronal damage lading to DN. Poly-ADP ribose polymerase (PARP) mediated NADH/ATP depletion can lead to neuronal dysfunction due to failure of various energy dependent processes in neurons. (ERK: extracellular related kinase, IL-6: interleukin-6, iNOS: inducible nitric oxide synthase, COX-2: cyclooxygenase-2, TGF-β: transforming growth factor-β, and PAI-1: plasminogen activator inhibitor-1.)

Figure 2

Crosstalk between oxidative stress and inflammation. Hyperglycemia mediated oxidative stress and inflammatory pathways are known to interact with each other at various levels. ROS activates nuclear factor (erythroid-1) related factor (Nrf2) by directly oxidising the thiol residues on kelch-like ECF associated protein (Keap-1). Nrf2 then migrates into the nucleus to activate antioxidant response elements (ARE) of genome. However, this Nrf2 activation by hyperglycemia is inhibited through extracellular related kinase activation (ERK). ROS also activates inhibitory kappa B kinase (IKK), which then phosphorylates the inhibitory kappa B protein (IκB); the latter combines with cytosolic NF-κB complex ant thus preventing its transcription. Phosphorylation of IκB labels it for ubiquitination and proteasomal degradation and, hence, releases NF-κB complex to enter into nucleus, which then expresses several proinflammatory mediators. Similarly, oxidative stress mediated c-JUN N terminal kinases (JNK) activation mediates the c-JUN component of activator protein-1 (AP-1) activation, which then combines with c-FOS subunit. The resulting AP-1 heterodimer binds with genome and increases production of various vascular inflammatory mediators. Oxidative stress mediated PARP activation also leads to inflammation through necrotic cell death. Nrf2 inhibits IκB degradation and thus prevents NF-κB mediated inflammation. NF-κB also prevents the Nrf2 signalling through histone deacetylases (HDAC3) recruitment (ASK-1-apoptosis signalling related kinase-1 and MCP-1-monocyte chemoattractant protein-1).